Diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology

doi:10.1016/j.eimc.2014.11.009

Enfermedades Infecciosas y Microbiología Clínica

Volume 33, Issue 5, May 2015, Pages 337.e1-337.e21

https://doi.org/10.1016/j.eimc.2014.11.009 Get rights and content

Abstract

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum β-lactamases and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial.

Clinically relevant questions were selected and the literature was reviewed for each of them. The information from the selected articles was extracted and recommendations were provided and graded according to the strength of the recommendations and quality of the evidence. The document was opened to comments from the members from the Spanish Society of Infectious Diseases and Clinical Microbiology, which were considered for inclusion in the final version.

Evidence-based recommendations are provided for the use of microbiological techniques for the detection of extended-spectrum β-lactamases and carbapenemases in Enterobacteriaceae, and for antibiotic therapy for invasive/severe infections caused by these organisms. The absence of randomised controlled trials is noteworthy; thus, recommendations are mainly based on observational studies (that have important methodological limitations), pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Resumen

La diseminación de Enterobacteriaceae multirresistentes en relación con la producción de β-lactamasas de espectro extendido y carbapenemasas es un importante problema de salud pública en todo el mundo. Tanto el diagnóstico microbiológico como el tratamiento de estas infecciones son complicados y controvertidos.

Los autores seleccionaron preguntas clínicamente relevantes, realizándose una revisión de la literatura para cada una de ellas; se obtuvo información de los artículos seleccionados y se realizaron recomendaciones que se clasificaron de acuerdo con la fuerza de la recomendación y la calidad de la evidencia. El documento estuvo abierto para los comentarios de los socios de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica, los cuales se consideraronpara su inclusión en la versión final.

Se proporcionan recomendaciones basadas en la evidencia para el uso de técnicas microbiológicas cara a la detección de β-lactamasas de espectro extendido y carbapenemasas en Enterobacteriaceae, y para el tratamiento antimicrobiano de las infecciones graves o invasivas causadas por estos microorganismos. Es llamativa la ausencia de ensayos aleatorizados, por lo que las recomendaciones se basan principalmente en estudios observacionales que tienen importantes limitaciones metodológicas, modelos farmacocinéticos y farmacodinámicos, y datos de estudios en animales. Además, se identificaron áreas prioritarias para la investigación futura.

Introduction

The dramatic worldwide increase in the rate of infections due to Enterobacteriaceae showing resistance to several first-line antimicrobial families in most countries over the last decade1, 2 is recognised as a public health crisis.³ The very limited therapeutic options available for these organisms are a real challenge. While several initiatives are being developed to facilitate the discovery and development of new antimicrobial agents and even non-antibiotic strategies for fighting infections due to multidrug-resistant (MDR) and extremely drug-resistant (XDR) organisms,3, 4, 5, 6 the most urgent question to answer is what is the best available treatment for patients suffering these infections. Infections due to MDR Enterobacteriaceae are associated with increased mortality compared with their susceptible counterparts, which is mainly related to the intrinsic difficulties of therapy of MDR isolates.7, 8 To the best of our knowledge, evidence-based guidelines with evidence-based recommendations on the treatment for infections caused by MDR and XDR Enterobacteriaceae have not been published.

The main objective of this guideline is to provide evidence-based recommendations for the microbiological diagnosis and treatment of invasive infections caused by MDR and XDR Enterobacteriaceae, and specifically those producing the most epidemiologically and clinically important mechanisms of resistance. Additionally, areas for future research are identified.

This guideline is intended to be useful for all clinical microbiologists, for clinicians in direct charge of patients with the infections covered, and for consultants such as infectious diseases specialists, clinical microbiologists, hospital epidemiologists, and pharmacists, as well as policy makers in the field of antibiotic stewardship and quality-of-care professionals. It is the intention of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) to review these guidelines in 2016 or before in case of substantial changes in evidence.

Section snippets

Methodology

This guideline was committed by SEIMC to a multidisciplinary group of Spanish clinicians and clinical microbiologists expert in the field. The authors selected a number of clinical questions by consensus based on their perceived clinical importance. Then a systematic review of the literature was performed in PubMed for each of them. The abstracts of the selected articles were read, and those referring to the questions were selected for full review. References from these articles were also

Microbiological diagnosis

The document will focus on ESBL- and carbapenemase-producing Enterobacteriaceae because these were considered the most relevant resistance mechanisms from both clinical and epidemiological points of view. The terms used in the literature review are specified in Table 2. No universal phenotypic or genotypic method exists which precisely embrace all ESBLs or carbapenemases types. The selected method to use will depend on the sample (surveillance or clinical), local prevalence, microorganism,

When should empirical treatment of MDR Enterobacteriaceae be considered?

It is well known that initial inappropriate antimicrobial therapy of severe infections leads to an increased morbidity and mortality.59, 60 Adequate therapy of severe infections caused by ESBL, plasmid-mediated AmpC or carbapenemase-producing Enterobacteriaceae is challenging, as many of the main agents typically used for infections caused by susceptible microorganisms are inactive. This may lead to extensive use of broad spectrum antibiotics, which would contribute to selection of further

Priority areas for future research

The panel selected the following areas as priorities for future research:

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Randomised trials comparing the clinical impact of the use of rapid diagnostic techniques in antibiotic use and clinical outcomes of patients with invasive infections caused by ESBL and carbapenemase-producing Enterobacteriaceae.
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Randomised controlled trials comparing the efficacy and safety of BLBLI, temocillin, and cephamycins with that of carbapenems in the treatment of invasive infections caused by ESBL-producing

Microbiological diagnosis

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For detection of ESBL or carbapenemase-producing Enterobacteriaceae in surveillance samples, specific chromogenic media are recommended (BII); alternatively, molecular-based methods toward a specific target may be used (CIII).
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Confirmation of ESBL-producers should be performed in isolates showing after screening increased MIC or reduced inhibition zone to third generation cephalosporins according to either EUCAST or CLSI criteria by microdilution (Etest is to be also considered) or disk

Conflict of interest

JRB was consultant for MSD, AstraZeneca, Pfizer, Roche, Novartis, Astellas and Anchaogen; speaker for MSD, AstraZeneca, Pfizer, Novartis and Astellas; and received research grants from Novartis and Gilead. CG was speaker for Novartis, Pfizer and Astellas; and received a research grant from Astellas. JPH was speaker and consultant for MSD, Astellas, Astra-Zeneca, Novartis, Pfizer and Basilea. GB was speaker for Pfizer, Novartis, Astellas and Janssen; and received research grants from Pfizer. All

Acknowledgements

Supported by the Spanish Society of Clinical Microbiology and Infectious Diseases, and Ministerio de Economía y Competitividad, Instituto de Salud Carlos III – co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

We are grateful to Belén Padilla, Jose María Gutiérrez and Juan E. Losa for their valuable comments on the manuscript.

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International guidelines for the treatment of carbapenem-resistant Gram-negative Bacilli infections: A comparison and evaluation
2024, International Journal of Antimicrobial Agents
This study aimed to appraise clinical practice guidelines (CPGs) for the treatment of carbapenem-resistant Gram-negative Bacilli (CRGNB) infections and to summarise the recommendations.
A systematic search of the literature published from January 2012 to March 2023 was undertaken to identify CPGs related to CRGNB infections treatment. The methodological and reporting quality of eligible CPGs were assessed using six domains of the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool and seven domains of the Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist. Basic information and recommendations of included CPGs were extracted and compared.
A total of 21 CPGs from 7953 relevant articles were included. The mean overall AGREE II score was 62.7%, and was highest for “clarity of presentation” (90.2%) and lowest for “stakeholder involvement” (44.8%). The overall reporting quality of all of the CPGs was suboptimal, with the proportion of eligible items ranging from 45.7 to 85.7%. The treatment of CRGNB infections is related to the type of pathogen, the sensitivity of antimicrobial agents, and the site of infection. In general, the recommended options mainly included novel β-lactam/ β-lactamase inhibitors, cefiderocol, ampicillin-sulbactam (mainly for carbapenem-resistant Acinetobacter baumannii [CRAB]), and combination therapy, involving polymyxin B/colistin, tigecycline (except for carbapenem-resistant Pseudomonas aeruginosa), aminoglycosides, carbapenems, fosfomycin, and sulbactam (mainly for CRAB).
The methodological and reporting quality of CPGs for the treatment of CRGNB infections are generally suboptimal and need further improvement. Both monotherapy with novel drugs and combination therapy play important roles in the treatment.
Prognosis of urinary tract infection caused by KPC-producing Klebsiella pneumoniae: The impact of inappropriate empirical treatment
2019, Journal of Infection
Citation Excerpt :
In recent years, numerous centers worldwide have witnessed outbreaks of carbapenemase-producing Enterobacteriaceae infections, including Klebsiella pneumoniae carbapenemase (KPC) infections, making their adequate control and treatment a global priority.1 These infections are difficult to treat since they are usually resistant to all first-line drugs, which may explain the high mortality of these infections and the need for combination therapy in high-risk patients.2–5 inappropriate empirical therapy has been also associated with higher mortality in patients with sepsis and gram-negative bacteremia.2,3
There is scarce information on the prognosis of urinary tract infections (UTI) caused by KPC carbapenemase-producing Klebsiella pneumoniae (KPC-Kp).
To investigate the association between KPC-Kp aetiology and clinical failure and all cause mortality and to explore the impact of inappropriate empirical treatment.
This is a retrospective observational study of hospitalized patients with UTI due to K. pneumoniae. We explored clinical failure at day 21 and 30-day all-cause mortality using different models of adjusted analysis.
We analyzed 142 episodes of UTI; 46 episodes (32.4%) were due to KPC-Kp and 96 episodes (67.6%) were due to non-KPC-Kp strains (62 wild type and 34 EBSL producer). Clinical failure was more frequent in the KPC-Kp group (41.3% vs. 15.6%, p = 0.001). KPC-Kp aetiology and inappropriate empirical therapy were associated in the non-adjusted analysis with clinical failure. When analysed in separate adjusted models, both were found to be associated; inappropriate empirical treatment (OR 2.51; 95% CI, 1.03–6.12; p = 0.04) and KPC-Kp (OR 2.73; 95% CI, 1.03–7.22; p = 0.04) were associated with increased risk of failure. All-cause 30-day mortality was higher in patients with KPC-Kp UTI (39.1% vs. 15.6%, p = 0.002). Bacteraemia was more frequent in patients with KPC-Kp etiology (23.9% vs. 10.4%; p = 0.034). In both cases, the association was not confirmed in the adjusted analysis.
KPC-Kp UTI is associated with higher clinical failure and may be due to an increase in inappropriate empirical treatment.
Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae from urinary tract infections: Evolution of antimicrobial resistance and treatment options
2018, Medicina Clinica
Se analiza la presencia, a lo largo de los años en infecciones urinarias, de aislados de Escherichia coli y Klebsiella spp. productores de betalactamasa de espectro extendido (BLEE), y su sensibilidad a antibióticos.
Se realizó un estudio retrospectivo entre 2012 y 2016. La sensibilidad a ciprofloxacino, tobramicina, cefoxitina, fosfomicina, nitrofurantoína, cotrimoxazol y carbapenémicos se analizó mediante el sistema MicroScan^®.
Se procesaron 95.399 muestras y se aislaron 9.772 E. coli, 1.784 Klebsiella pneumoniae y 248 Klebsiella oxytoca. Las cepas con BLEE fueron más frecuentes en mujeres, aunque disminuyó durante 2015 y 2016 (65,7-67,2%). La prevalencia de K. pneumoniae BLEE aumentó todos los años (28,1% en el 2016). La prevalencia media de E. coli BLEE fue del 10,5%, con escasas oscilaciones. Las mayores resistencias ocurrieron a ciprofloxacino y cotrimoxazol, 89,5 y 94,7% en 2015, respectivamente, y las menores a imipenem. Fosfomicina y nitrofurantoína fueron muy activos sobre E. coli BLEE.
E. coli y K. pneumoniae con BLEE fueron prevalentes y, sobre todo esta última, con una importante resistencia a ciprofloxacino y cotrimoxazol. La sensibilidad a imipenem fue elevada.
A study of the susceptibility to antimicrobials of the extended spectrum beta-lactamase phenotypes (ESBL) in Escherichia coli and Klebsiella spp. was performed to discover the evolution of this type of resistance from urinary tract infections.
A retrospective study was carried out between 2012 and 2016. Susceptibility to ciprofloxacin, tobramycin, cefoxitin, fosfomycin, nitrofurantoin, co-trimoxazole, and carbapenems was analyzed using MicroScan^® system.
A total of 95,399 samples were processed and 9,772 E. coli, 1,784 Klebsiella pneumoniae and 248 Klebsiella oxytoca were isolated. ESBL strains were more frequent in women, although they decreased during 2015 and 2016 (65.7-67.2%). The prevalence of K. pneumoniae ESBL increased annually (28.1% in 2016). The average prevalence of E. coli ESBL was 10.5% with few oscillations. Higher resistance occurred to ciprofloxacin and cotrimoxazole, 89.5 and 94.7% in 2015, respectively, and there was lesser resistance to imipenem. Fosfomycin and nitrofurantoin were very active on E. coli ESBL.
ESBL producing E. coli and K. pneumoniae were prevalent, especially the latter, with a significant resistance to ciprofloxacin and cotrimoxazole. Susceptibility to imipenem was high.
Protocol for the empirical treatment of urinary tract infections
2018, Medicine (Spain)
Las infecciones del tracto urinario representan una de las causas infecciosas más frecuentes tanto a nivel comunitario como a nivel nosocomial y relacionado con la asistencia sanitaria. Habitualmente no son infecciones graves, pero sí que condicionan un uso frecuente y muchas veces innecesario de antibióticos, con el riesgo de selección de mecanismos de resistencia, además de los posibles efectos secundarios de un tratamiento evitable.
Representa el aislamiento de un uropatógeno en recuento significativo en una muestra de orina en una persona asintomática. Su diagnóstico y tratamiento es de especial interés en la mujer gestante y previo a la realización de un procedimiento urológico de alto riesgo.
Son infecciones urinarias sintomáticas en las que es importante conocer la evidencia disponible de diagnóstico y de tratamiento para disminuir el riesgo de recurrencias y el uso adecuado de antibióticos.
Situación clínica definida por la presencia de al menos 2 episodios en los 6 últimos meses o 3 o más episodios en el año previo. Representa un problema relativamente frecuente en el que las estrategias preventivas, adaptadas a cada situación clínica, son muy importantes.
Urinary infections are one of the most common healthcare-related infections both at community and nosocomial level. They are not usually serious but they do incur a frequent and often unnecessary use of antibiotics, with the risk of resistance mechanisms, and possible side effects of treatment that could have been avoided.
This is when a high uropathogen count is found in the urine of an asymptomatic person. Its diagnosis and treatment is of particular interest in pregnant women and after undertaking a high-risk urological procedure.
These are symptomatic urinary tract infections and it is important to be aware of the available evidence for diagnosis and treatment to reduce the risk of recurrence and use antibiotics appropriately.
A clinical situation defined by at least 2 episodes in the course of the past 6 months or 3 or more in the previous year. This is a relatively common problem where preventive strategies, adapted to each clinical situation, are very important.
Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients
2017, International Journal of Infectious Diseases
Citation Excerpt :
Nevertheless, these data have to be interpreted with caution since the sample size of the study does not allow adjusting for other possible variables, although it seems reasonable to think that patients with clinical cure will be at lower risk of mortality. In previous studies combination treatment has been associated with a better prognosis in patients with bacteremia caused by carbapenemase-producing Klebsiella pneumoniae (Tofas et al., 2016; Tumbarello et al., 2012; Paño et al., 2014; Rodríguez-Baño et al., 2015). However, we found no difference in mortality when comparing the group of patients who received combination therapy to those who received monotherapy.
The primary objective was to describe clinical features, treatment and outcomes in patients with carbapenemase-producing Enterobacteriaceae (CPE) bacteremia. Additionally, patients treated with ceftazidime/avibactam (study group) were compared to the rest of the patients (comparator group) to determine the influence of the treatment in both crude mortality and clinical cure.
Multicenter and retrospective study that included patients with hematologic malignancies who had CPE bacteremia. A bivariate analysis was performed to compare the clinical variables between the study group and the control group.
31 patients were included. Bacteremia was considered primary in 14 (45%) patients. Overall crude mortality at 30 days was 45.2% (n = 14). Mortality was more frequent when septic shock (78.6% vs 11.8%; p > 0.001) and higher Pitt score (6 + 14 vs 1.5 + 4; p < 0.01) were present. 8 patients (25.8%) received treatment with ceftazidime/avibactam. No significant differences in crude mortality were found between study and comparator groups (p = 0.19). In contrast, patients in study group had higher clinical cure rates than the comparator group within 14 days of initiating treatment (85.7% vs. 34.8%, respectively, p = 0.031).
CPE bacteremia is associated with high mortality in patients with hematologic malignancies. Ceftazidime/avibactam may be an effective alternative for treating these patients.
Characterisation of patients with carbapenemase-producing Klebsiella isolates in a third-level paediatric hospital in Bogota, Colombia
2016, Infectio
Describir las características clínicas de pacientes pediátricos con aislamiento de Klebsiella productora de carbapenemasa.
Entre 2012 y 2015 se realizó un estudio descriptivo que incluyó a pacientes de 0-18 años (media 4,8 años), todos con aislamientos de Klebsiella productora de carbapenemasa.
Se documentó infección en 21 pacientes; el 81% tenía antecedente de hospitalización en los 6 meses previos y el 67% de antibioticoterapia. Los sitios de aislamiento fueron sangre (48%), orina (33%), líquido pleural (9%), líquido peritoneal y tráquea (5%). El 95% de los pacientes tenía comorbilidad asociada; el 81% de los aislamientos correspondió a infecciones nosocomiales. Los servicios de hospitalización fueron UCIP 43%, Pediatría General 29%, Oncología, Unidad Neonatal y Urgencias 9,5% cada uno. El 81% de los aislamientos presentó corresistencia a otros antimicrobianos. El tratamiento definitivo se realizó con monoterapia en un 19%, terapia doble en un 28,5% y terapia triple en un 23,8%. La mortalidad fue del 24%.
To describe the clinical characteristics of paediatric patients with carbapenemase-producing Klebsiella isolates.
Between 2012 and 2015, we conducted a descriptive study that included patients aged 0-18 years (mean 4.8 years), all with Klebsiella carbapenemase-producing isolates.
The infection was documented in 21 patients, 81% of the patients had a history of hospitalisation in the last 6 months and 67% had undergone antibiotic therapy. The isolation sites were blood (48%), urine (33%), pleural fluid (9%), peritoneal liquid and trachea (5). Ninety-five percent of the patients had associated comorbidity; 81% of the isolates corresponded to nosocomial infections. The hospital departments were the paediatric intensive care unit (43%), general paediatrics (29%), oncology, neonatal unit and emergency department (9.5% each). Eighty-one percent of the isolates had co-resistance to other antimicrobials. Definitive treatment was performed with monotherapy in 19% of the cases, double therapy in 28.5% and triple therapy in 23.8%. The mortality rate was 24%.

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Abstract

Resumen

Introduction

Section snippets

Methodology

Microbiological diagnosis

When should empirical treatment of MDR Enterobacteriaceae be considered?

Priority areas for future research

Microbiological diagnosis

Conflict of interest

Acknowledgements

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Distribution of extended-spectrum beta-lactamases, AmpC beta-lactamases, and carbapenemases among Enterobacteriaceae isolates causing intra-abdominal infections in the Asia-Pacific region: results of the Study for Monitoring Antimicrobial Resistance Trends (SMART)

Antimicrob Agents Chemother

Performance of chromID^® CARBA medium for carbapenemases-producing Enterobacteriaceae detection during rectal screening